Roughly 17,000 people in the United States will suffer a spinal cord injury (SCI) this year. For the vast majority of them, the injury will leave them incapable of walking or, if they have suffered a cervical SCI, entirely dependent upon others for assistance in all of their activities of daily living from feeding to personal care. More importantly, chances of improvement as a result of therapeutic interventions are bleak since there are no approved therapies that enhance functional outcomes. The cost to these individuals, and to society as a whole, are quite large as SCI often occurs in adults in their peak earning years. The vast majority of therapeutic interventions currently being tested are developed for use in the acute period from hours to days after injury. For those not fortunate enough to be in the right hospital within 72 hours of their injury, there are essentially no therapeutic options being explored outside of the surgical standard of care. We are developing a small molecule inhibitor of ROCK, BA-1049, which could be widely available, even outside of the acute hospital setting. BA-1049 is a small molecule inhibitor of ROCK2, which shows favorable safety characteristics after repeat administration, is orally available, penetrates the nervous system, and has good drug-like properties. ROCK2 is a protein kinase that is highly expressed in the central nervous system and is overactivated following spinal cord injury. The ROCK2 signaling pathway is overactivated days to weeks after SCI and as such, targeting this kinase with BA-1049 could promote recovery if BA-1049 were to be used days to weeks after injury. We propose to use a rat spinal cord contusion injury model to establish the dose of BA-1049 capable of restoring normal levels of ROCK signaling after oral administration. Based on these results, we will undertake a proof-of-concept study for efficacy of the compound in improving functional recovery after thoracic SCI. Once we have investigated acute use, we will establish whether BA-1049 can improve functional outcomes when administered over two different time frames post-injury, a sub-acute time frame and a sub-chronic time frame. We will also examine regenerative growth of descending fiber tracts after injury and treatment with BA-1049, with a focus on the tracts that are sources of motor and neuromodulatory control. Additionally, we will carry out non-clinical GLP safety toxicology studies that will be required by FDA prior to first-in-human studies. Our overall plan is to develop BA-1049 as an orally available, pro-regenerative treatment for SCI that can be administered for days or weeks after injury to be used in concert with other modalities such as physical therapy to maximize functional outcomes.